The present invention relates to a novel, advantageous process for the production of isosorbide-5-nitrate (1,4-3,6-dianhydroglucitol-5-nitrate) of formula 1. ##STR1##
Isosorbide-5-nitrate (5-ISM) is a well-known compound whose therapeutical application has recently been intensively investigated. The starting point of this interest was the observation that isosorbide-2,5-dinitrate (ISD), a well established substance used in the treatment of coronary diseases, is rapidly metabolized in the organism and that isosorbide-2-nitrate (2-ISM) and isosorbide-5-nitrate (5-ISM) occur as metabolites. [S. F. Sisenwine and H. W. Ruelius, J. Pharmacol. Exp. Ther. 176,269 (1971); W. H. Down et al., J. Pharm. Sci. 63,1147 (1974); L. F. Chasseaud et al., Eur. J. Clin. Pharmacol. 8,157 (1975)].
Moreover, it has been shown that the metabolites 2-ISM and 5-ISM in principle have the same effect as the mother substance ISD [R. L. Wendt, J. Pharmacol. Exp. Ther. 180,732 (1972); M. G. Bogaert et al., Naunyn-Schmiedebergs Arch. Pharmacol. 75, 339 (1972); M. Stauch et al., Verh. Dtsch. Ges Kreislaufforsch. 41, 182 (1975); D. Michel, Herz-Kreislauf 8,444 (1976)].
Compared with ISD it has been further observed that 2-ISM and 5-ISM are advantageously distinguished by various therapeutically important parameters such as resorption behaviour, half life, toxicity, oral applicability and the like. Instead of ISD it may therefore be expedient to administer the mononitrates, especially isosorbide-5-nitrate, to treat heart diseases such as angina pectoris. This application, however, requires an economic, technically feasible source of the pure substances.
The 5-ISM syntheses that are presently available are not satisfactory with respect to technical practicability, yield and costs. The following methods are known:
Isosorbide is directly nitrated whereby a mixture of ISD, 2-ISM, 5-ISM and unchanged isosorbide, of varying composition, results. This mixture has to be separated into its individual components by time consuming and costly chromatographic separation procedures that cannot be carried out on an industrial scale. The yield of 5-ISM obtained in this way is so small and the isolation method is so time consuming and expensive that no practical importance can be attached to this method [I. G. Csizmadia and L. D. Hayward, Photochem. Photobiol. 4,657 (1965)].
Another procedure according to which isosorbide is first converted into the 2,5-dinitrate and then partially hydrolyzed, results again in the mixture of ISD, 2-ISM and isosorbide mentioned above, the separation and isolation of which is not economically viable [M. Anteunis et al., Org. Magnet. Resonance 3, 693 (1971)].
DOS No. 2 751 934 and the corresponding U.S. Pat. No. 4,065,488 describe the following procedure: Isosorbide is acylated with an acid chloride or an acid anhydride whereby a mixture of isosorbide-2-acylate, isosorbide-5-acylate, isosorbide-2,5-diacylate and isosorbide is obtained. Isosorbide is extracted from this mixture in order to prevent the formation of ISD, a potentially explosive substance, in the subsequent nitration step. The remaining mixture of isosorbide-2-acylate, isosorbide-5-acylate and isosorbide-2,5-diacylate is nitrated with nitric acid yielding a mixture of isosorbide-5-acylate-2-nitrate, isosorbide-2-acylate isosorbide-5-nitrate and isosorbide-2,5-diacylate. By a selective hydrolysis a mixture of isosorbide-2-nitrate, isosorbide-5-nitrate and isosorbide results. The latter has to be removed again by extraction before isosorbide-2-nitrate is isolated as the main component from the remaining residue by crystallizing from suitable solvents. Isosorbide-5-nitrate remains in the mother liquors. There is a lack of any instructions concerning its isolation.
All previously mentioned procedures are characterized by the fact that a selective preparation of isosorbide-5-nitrate is not possible because of the formation of mixtures which then have to be separated into their individual components by suitable separation procedures. This is, however, a costly and time consuming process. The desired final product can only be obtained in a poor yield and thus an economical production is not possible.
The first process for a selective preparation of isosorbide-5-nitrate was recently published in DAS No. 2 903 927. According to this process, isomannide is converted into the corresponding isomannide-2-ester by means of a halide or anhydride of a suitable sulfonic acid or carboxylic acid. The reaction of the isomannide-2-ester with an alkaline salt or an ammonium salt of a benzoic acid or with tetrabutyl ammonium acetate or tetrabutyl ammonium formate provides an isosorbide-2-ester. This is then esterified in a known manner with nitric acid and the resultant isosorbide-2-ester-5-nitrate is then partially hydrolyzed, under cleavage of the 2-ester group, thus yielding isosorbide-5-nitrate. This process possesses advantages over previously known ones in as much as only one defined product results. With respect to expense and economy, however, this procedure is unsuitable. The starting material, isomannide, is at present essentially more difficult to obtain and also much more expensive than isosorbide. Moreover, this procedure consists of four steps and is therefore labour and apparatus intensive as well as time consuming. Finally, the overall yield of this four step method is less than 50 % of the theoretical yield.
It is generally known that the following main procedures can be considered for the acylation of isosorbide:
1. esterification of isosorbide with acids
2. transesterification of isosorbide with acid esters
3. acylation of isosorbide with acyl halides
4. acylation of isosorbide with anhydrides
As a diol, isosorbide has two points of attack. Accordingly any acylation attempt results in a mixture of isosorbide, isosorbide-2-acylate, isosorbide-5-acylate and isosorbide-2,5-diacylate with varying amounts of the individual components. The composition of the product mixture varies depending on the production method and the reaction conditions. Results of systematic investigations of this subject are not yet available; only some individual observations have been reported.
For example, DOS No. 2 751 934 mentioned previously describes a mixture of the four possible components obtained by acylation of isosorbide with acid anhydrides in the presence of acidic catalysts but does not describe the composition of the mixture.
The conversion of isosorbide with 1 mol of acetic acid anhydride in pyridine produced isosorbide-2-2- and 5-monoacetate in a ratio of approx. 1.7:1 as well as isosorbide-2,5-diacetate as the main product (K. S. Buck et al., Carbohydrates Res. 2, 122 (1966)). In the presence of pyridine hydrochloride a product ratio of 2-acetate/5-acetate of approx. 1:3.6 was achieved, however, again in a lesser amount, along with 2,5-diacetate. In neither of the isosorbide monoacetates did acyl migration occur due to the influence of pyridine, with or without the addition of pyridine hydrochloride.
Therefore there is still a demand for manufacturing procedures which provide, over a few steps, isosorbide-5-nitrate in improved yields and in which inexpensive starting materials are used.